Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

Many transformations that afford important categories of organic building blocks useful for the synthesis of pharmaceutical intermediates and APIs cannot be performed due to hazardous conditions. Reactions that require the use of unstable reagents lead to the formation of highly reactive intermediates, and those that are highly exothermic typically are not suitable for implementation on a large scale because of the hazards they pose.

	Research is ongoing in both the industrial and academic setting to develop alternative approaches that will enable these transformations to be performed safely on a commercial scale. Such approaches include the development of new forms of hazardous reagents that are stable and can be readily manipulated in the plant setting; identification of new reaction conditions, such as the use of flow chemistry, to reduce the quantities of hazardous reagents and/or provide highly controlled conditions for energetic reactions; and the identification of entirely new routes that do not have any of these issues.

	Examples of recent approaches to overcome hazardous transformations are described in the following sections.
	
	


	In the Vilsmeier (or Vilsmeier-Hack) reaction, aryl aldehydes and ketones are obtained from substituted amides via their reaction with phosphorous oxychloride and electron-rich aromatic compounds. The substituted chloroiminium ion formed from the reaction of the substituted amide with phosphorous oxychloride is referred to as the Vilsmeier reagent (VR). While this reaction can provide a wide range of interesting carbonyl compounds, its use on a large scale can be difficult, because VRs are often irritants and also hazardous reagents due to their high thermal energies of decomposition.

	Researchers at Novartis Pharma employed flow chemistry to address this issue (1). They achieved the in-line formation and immediate consumption of VRs using a combination of batch and flow technologies and applied the new process to the synthesis of the anti-diabetic drug vildagliptin.

	Researchers at AMRI also performed a potentially hazardous cyclopropane ring-opening reaction in a continuous-flow reactor to increase the safety of the process (2). Subsequent copper-mediated Diels-Alder and palladium-catalyzed Negishi coupling reactions were also used in the optimized synthesis of taxadienone on a decagram scale.

	At Bristol-Myers Squibb, a hazardous analysis of a reaction involving the conversion of a tertiary alcohol to a hydroxypyrrolotriazine intermediate identified the potential for thermal runaway (3). To mitigate this potential, a continuous oxidative rearrangement process was developed that involves the mixing of three different, stable feed streams in a specific order using in-line static mixers. A “plug flow” design achieved using heat exchangers ensures sufficient residence times for completion of the reaction. The continuous process has been employed on the pilot plant and commercial manufacturing scales for the production of the investigational liver cancer drug brivanib alaninate.


	Advances in process analytical technology (PAT) not only help speed up process development and optimization, they can also facilitate the control, and thus increase the safety, of synthetic organic reactions. Researchers at Merck Sharp & Dohme recently reported the successful application of PAT for determining the appropriate timing of reagent addition and reaction quenching (4). The technologies discussed included process video microscopy (PVM), a new focused-beam reflectance measurement (FBRM) method, miniature process infrared (IR) spectroscopy, and a flow IR sensor. PVM was used as a nondestructive method for analyzing particle morphologies in real time, while the new FBRM technique has improved reliability due to its greater resistance to probe fouling. The miniaturized IR system was found to be easier to use at scale-up and more robust, and the miniature IR flow sensor was a more cost-effective tool with a faster response, and thus useful for continuous flow processes.

	The IQ Consortium, an organization of pharmaceutical and biotechnology companies with the mission of advancing science-based and scientifically-driven standards and regulations for pharmaceutical and biotechnology products worldwide, also recently reported on the current state of PAT use in the development of APIs (5). In the paper, the authors point out that PAT can minimize the hazards posed to operators when sampling hazardous materials and also provide more reliable data on processes that involve the use of hazardous materials. Through greater process understanding, increased process control-often through the use of simplified monitoring and control systems-is possible at the commercial production scale.


	One of the most effective methods for eliminating the concerns associated with hazardous reagents is to develop stable derivatives or totally new alternatives that accomplish the desired transformation without the safety concerns of the original compounds. Several examples have appeared in literature recently.

	Michael Willis at the University of Oxford developed a method for the synthesis of sulfonamides via 

 formation of intermediate sulfinates from magnesium-, lithium-, and zinc-based reagents and DABSO, a surrogate for sulfur dioxide (6). The sulfinates were reacted with N-chloroamines, which were also generated in situ by reacting amines with aqueous bleach. While sulfonamide groups are present in biologically relevant compounds, they are often accessed through the corresponding sulfonyl chlorides, which can be unstable. The new method provides a route that avoids sulfanyl chlorides. Primary and secondary amines, anilines, and amino acids were all suitable for the reaction, which proceeded most efficiently with Grignard reagents.

	Sodium metal is often used effectively for Birch reductions and the reduction of esters (Bouveault-Blanc reduction), but does have associated safety concerns at larger scale given the pyrophoric nature of sodium metal and the volatility of ethanol. Researchers at the University of Manchester and Pentagon Fine Chemicals reported that a dispersion of sodium metal particles with diameters ranging from 5-15 μm in a mineral oil is a nonpyrophoric, free-flowing powder alternative that can be handled in air and provides results similar to sodium metal (7). In particular, the Bouveault-Blanc reduction was found to proceed in high yields at 0 °C in hexane for a wide range of aliphatic ester substrates with 2.5 equivalents of isopropanol rather than ethanol and just 4.5 equivalents of the sodium dispersion. Notably, alkenes, aryl amines and fluorides, acidic protons, and sterically hindered carbon centers were tolerated

	Direct aryl C-H chlorination is another desirable reaction for the preparation of aromatic chlorides, but the most reactive methods typically require the use of hazardous reagents such as chlorine (Cl

). Milder reagents are available, including N-chlorosuccinimide (NCS) and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), but their applicability is limited due to their reduced reactivity.

	Other reagents that have been employed also suffer from unattractive features such as toxicity, hydroscopicity, light/heat sensitivity, and explosive properties among others. Phil S. Baran and colleagues at The Scripps Research Institute and Bristol-Myers Squibb have developed the guanidine-based chlorinating reagent 2-chloro-1,3-bis(methoxycarbonyl)guanidine (CBMG), which they refer to as Palau’chlor, as an alternative for the mild and safe direct chlorination of nitrogen-containing heterocycles and certain arenes, conjugated π-systems, sulfonamides, and silyl enol ethers (8). The new reagent is an air-stable solid that is thermally stable below 100 °C, yet achieves transformations that have only been possible in the past with highly reactive, hazardous chlorinating reagents. Importantly, the cost of the reagent and its functional group tolerability are similar to that of NCS.

, 19 (4), 551-554 (2015).
	2. S. G. Krasutsky, et al., 

. 19 (1), 284-289 2015.
	3. Thomas L. LaPorte, et al., 

. 18 (11), 1492-1502 (2014).
	4. George Zhou, et al., 

. 19 (1), 227-235 (2015).
	5. John D. Orr ,et al., 

. 19 (1), 63-83 (2015).
	6. M.C. Willis, et al., Angew. 

. 54 (4), 1168-1171 (2015)
	7. D.J. Proctor, et al., 

. 79 (14), 6743-6747 (2014).
	8. Phil S. Baran, et al., 

:
	When referring to this article, please cite it as C. Challener, "New Ways Around Hazardous Reagent Chemistry," 

Articles

Safer reagents and reaction conditions are making many hazardous transformations possible.

New Ways Around Hazardous Reagent Chemistry

Continuous processing is attracting attention in the manufacture of both small-molecule drugs and biopharmaceuticals. In small-molecule manufacturing, flow chemistry has many advantages, including increased development speeds, improved product and process consistency and thus product quality, greater process safety when employing hazardous chemistries, the opportunity to perform reactions that cannot be run under batch conditions, and reduced capital investment and operating costs. 

	Continuous downstream processing operations offer many similar advantages, and there has been more focus on integrating continuous downstream processes with continuous flow synthesis. While many downstream processes can be readily adapted to run continuously, such as extraction, phase separation, and distillation, others-particularly those related to solids handling-present greater challenges.

	Several research groups supported by industry have focused on continuous crystallization. The Center for Innovative Manufacturing in Continuous Manufacturing and Crystallization (CMAC), for instance, has support from founding members such as GlaxoSmithKline, Novartis, and AstraZeneca and is developing continuous processes for all stages of crystallization that are efficient, cost-effective, scalable, sustainable, and precisely control the form, size, shape, purity, surface structure, and functionality of crystallized drug intermediates and APIs. Researchers at the Novartis-MIT Center for Continuous Manufacturing have investigated methods for the direct crystallization of APIs on polymer excipient surfaces and the incorporation of continuous crystallization processes within an integrated continuous manufacturing pilot plant, which requires careful selection of appropriate process analytical technology (PAT).

One of the advantages that can be realized by implementing integrated continuous processing is reduction of the number of processing steps typically required for completion of the same process in batch equipment. For crystallization processes, direct crystallization of a pharmaceutical intermediate or API on the surface of a polymeric excipient can lead to the simultaneous separation of impurities and formation of a drug-excipient composite. This result may cause the elimination of several solid-handling steps that are typically required for the downstream processing of solid products, according to Bernhardt L. Trout, the Raymond F. Baddour professor of chemical engineering at MIT and director of the Novartis-MIT Center for Continuous Manufacturing. “If crystallization can provide a product with the appropriate physical properties, it is possible to eliminate the need for milling, granulation, and other processes,” he says.

Importance of heterogeneous nucleation
	

Heteronucleation involves the formation of crystal nuclei at a solid-liquid interface and can be employed to control nucleation and, potentially, polymorphism, which is important for the production of APIs with stable forms (1). There is some evidence, according to Trout, that the surface morphology of the solid affects the crystallization process. “In particular, the use of nano-patterned substrates can affect not only the nucleation kinetics, but phase stabilization, polymorphism, and the orientation of the resultant crystals,” he adds.

Heteronucelation of a single compound using different polymeric substrates can provide access to a wide range of polymorphs for that compound, because the different surface morphologies of the polymers result in different interactions at the polymer-crystal interface (1). Nanoimprinting of polymers provides a way to impart specific surface geometries that can be used to influence nuclei formation and ultimately polymorphism, according to Trout. “Our supposition was, therefore, that nanoimprinting of polymers that already provide favorable surface-solid interactions to create surface geometries that lead to nanoconfinement should allow for control of crystallization behavior,” he comments. It should be noted that the functionality of the polymer and whether it is more hydrophilic or hydrophobic determines the interactions between the solute and the polymer surface, and thus the crystallization process.

	Trout and his colleagues examined a range of polymer types to determine their effects on this templated crystallization process. To create the engineered polymer surfaces, a rigid, flat silicon mold with nanometer-sized and mono-dispersed pillars of varying angles was fabricated using interference lithography. Negatives of the mold were then transferred to polymer films using nanoimprint lithography. “With this method, it is possible to create both hydrophobic and hydrophilic polymer surfaces with nanopores of many different shapes and sizes. By considering the structure of the API, it may therefore be possible to choose a specific polymer and nanopore structure that will result in crystallization of a specific polymorph of the API, even metastable forms,” Trout notes. For example, favorable interactions can be observed by matching the surface geometry angles with the angles between dominant faces of the desired polymorph of a compound, according to Trout. Enhanced nucleation rates and alternation of the polymorph distribution can result.

	Initially the biocompatibility of the polymers was not considered; eventually the researchers focused solely on polymers that have generally-recognized-as-safe (GRAS) status given that these polymers can be used as excipients in final drug formulations, says Trout. The processability and solubilities of the polymers were also considered. Pharmaceutically acceptable organic solvents were also screened to find an appropriate crystallization solvent.

Effective continuous crystallization in an integrated process
	

Continuous crystallization techniques in the pharmaceutical industry are typically developed as stand-alone processes, but in many cases, the goal will be to develop a fully integrated continuous process involving flow chemistry, purification, and final formulation. In such a setting, the crystallization process can be affected by events that occur upstream, and careful control of the crystallization conditions is required to ensure that all critical material attributes and critical process parameters are met on a continual basis.

	Trout and several colleagues at MIT have investigated the implementation of continuous crystallization in the pilot plant developed at the Novartis-MIT Center, which is designed for integrated continuous manufacturing (ICM) of pharmaceutical compounds (2). “The most significant result of this study, which involved the two-stage continuous crystallization of aliskiren hemifumarate as part of an ICM pilot plant, was the determination that the use of a combination of different PAT tools and automated control loops was sufficient to maintain operational performance within specifications for extended periods of time,” Trout states. In fact, the continuous reactive crystallization was performed for more than 100 hours in the integrated process, providing product with a purity >99% and a yield of 91.4% (2).

1. V. Lopez-Mejías, A. S. Myerson, and B. L. Trout, 

, 13 (8) 3835−3841 (2013).
	2. H. Zhang et al., 


	When referring to this article, please cite as C. Challener, “Considering Continuous Crystallization,” 

Research groups supported by industry tackle the challenges of continuous crystallization and process analytical technology.

Advances in Continuous Crystallization

	In September 2011, the US Government Accounting Office (GAO) published a report on the challenges that FDA faced in assuring the safety of the API supply chain given that reliance on APIs produced by foreign manufacturers has risen dramatically and the complexity of the global pharmaceutical supply chain has increased significantly over the past two decades (1). The report found that while FDA had increased inspections of foreign API manufacturers (up 27% from 2007 to 2009, for example), its rate of inspection for foreign establishments was still far below that for domestic manufacturers. In addition, most foreign inspections were scheduled far in advance, conducted under controlled circumstances, and typically occurred during much shorter time frames. GAO also determined that FDA still lacked important information about foreign API manufacturers (1).

	On a positive note, GAO recognized that FDA had begun to implement initiatives designed to improve its oversight of the drug supply chain, including increased training by overseas offices, the development of programs for control of APIs and other drug products entering the United States, and a push for risk-based inspections rather than a set schedule (1). The GAO concluded, however, that FDA needed to implement changes more rapidly to better assure the safety of drugs on the US market (1).

	Since that report, new legislation has affected FDA ‘s ability to schedule and conduct inspections of API manufacturers. As a result, inspections of foreign manufacturers have increased dramatically--along with warning letters--while inspections of domestic manufacturers have decreased.


	The most important piece of legislation affecting FDA ‘s ability to improve the safety of the pharmaceutical supply chain is the Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on July 9, 2012. The Generic Drug User Fee Amendments (GDUFA), included as part of FDASIA, instituted a Generic Drug User Fee Program that was agreed to by FDA and the generic-drug industry, specifically the Bulk Pharmaceutical Task Force (BPTF) of the Society of Chemical Manufacturers and Affiliates (SOCMA), the European Fine Chemicals Group (EFCG), and the Generic Pharmaceutical Association (GPhA).

	The user fees are intended to provide additional funding for FDA ‘s drug approval and inspection efforts with the goal of increasing the safety of generic drugs and the ingredients used to produce them, increase the speed of the drug approval process, and the transparency of the industry. One of the main goals of GDUFA is to ensure that foreign facilities are inspected at a rate equal to that of domestic facilities. The fees raised through GDUFA have enabled FDA to hire approximately 1000 additional employees, making it possible for the agency to complete more inspections and speed up the approval process for abbreviated new drug applications (ANDAs) and the review of drug master files (DMFs).


	Several other aspects of the FDASIA legislation have also impacted the API and formulated-drug supply chain. For instance, FDASIA requires FDA to identify facilities involved in the manufacture of generic drugs and associated APIs. “Prior to FDASIA, FDA didn ‘t know how many facilities were producing formulated drugs or APIs in the US, let alone how many companies around the world were manufacturing APIs and formulated drugs and exporting them to the US,” says John DiLoreto, executive director of BPTF. Before the self-registration process began, the industry estimated that there were 1700-2000 manufacturing sites around the world. After the registration process was complete, that number was reduced to approximately 1300. DiLoreto believes that some consolidation of manufacturing plants occurred as companies looked to reduce the GDUFA fees they would have to pay by consolidating operations.

	In the most recent report on foreign and domestic drug establishments issued by FDA (2), the agency identified a total of 12,949 registered drug establishments in 2014, including 9330 domestic and 3619 foreign (slightly up from 12,613 in 2013. Of those 12,949 facilities, 4383 were registered as finished drug product (FDP) establishments, and 1495 were registered as API establishments. (If a site produces both finished drug products and APIs, it is placed in the FDP category.) The remaining 7071 establishments fell into the “other” category, which includes facilities that produce, compound, or process medical gases, medicated feed, and some biologic drugs.

	FDASIA also grants FDA the authority to confiscate and destroy unsafe APIs and drug products being imported into the US. With its increased ability to track the manufacturing activities and inspection histories of API and drug manufacturing sites, the agency can determine if APIs or finished drug products were produced at a facility that has not been FDA-inspected or is not in compliance. The agency has also published guidance on what conduct it considers as delaying, denying, limiting, or refusing inspection, actions that can result in determination of a drug to be adulterated. In addition, under GDUFA, all drugs produced in an unregistered facility or in a facility for which the GDUFA fees have not paid are considered “misbranded.”

	“Together, these new capabilities of the agency make it possible for potentially unsafe APIs and drug products to be removed from the marketplace completely,” DiLoreto says.

	FDA is also using the information on establishments to prioritize them according to the level of risk each represents. Rather than inspect facilities on a set schedule as was the case in the past-typically once every two and one-half years on average for domestic facilities and once every 10 years or more for foreign manufacturing sites-the agency now determines which facilities to inspect based on the overall level of risk they pose, which is determined using a model that takes into account inherent risk, outbreaks, recalls, adverse events, and compliance history (3). This move has led to a dramatic increase in foreign inspections and a concomitant decline in domestic inspections.

	In fiscal year (FY) 2014, the total number of foreign and domestic high-risk human drug inspections by FDA was 918, which exceeded the agency ‘s target of 750 (3). In FY 2013, 443 domestic and 365 foreign high-risk establishments were inspected (total of 808); 43 GMP-based warning letters were issued as a result of those inspections (4). Overall in FY 2013, FDA conducted 967 domestic and 604 foreign GMP inspections (3). In FY 2014, those numbers were 780 and 757.  FDA estimates that in both FY 2015 and 2016, there will be 591 domestic and 843 foreign inspections.

	Both the agency and the industry are adjusting to the risk-based inspection approach, according to DiLoreto. “When FDA first indicated that it would be decreasing domestic inspections so significantly, BPTF was initially concerned that domestic facilities would not be receiving inspections often enough, particularly those exporting to Europe, because the European Medicines Agency (EMA) requires pharmaceutical manufacturers importing products into the European Union to have had an inspection within the previous three years,” notes DiLoreto. The agency has addressed those concerns and established an agreement with EMA. “One of the primary goals of GDUFA was to achieve inspection parity between foreign and domestic facilities, but the change to a risk-based program allows FDA to better utilize resources,” he adds.


	An additional step in the right direction was made in December 2014 when FDA Commissioner Margaret Hamburg signed an agreement with Chinese officials to collaborate on inspections in China that builds on an initial agreement signed in 2007 (5). China also finally agreed to provide additional visas for more FDA inspectors, which will allow the agency to boost its number of employees from 13 to 33.

	FDA is working with EMA on joint inspections and trying to establish mechanisms for sharing of inspection data, according to DiLoreto. BPTF would like to eventually see EMA and FDA inspections results considered to be equivalent. There are, however, concerns on the part of some manufacturers about how confidential business information can be adequately protected under such a scenario.


	Despite the numerous advances that FDA has made in addressing concerns about APIs and formulated drugs manufactured overseas, there are still many challenges facing the agency. Some foreign governments still do not welcome the agency, and inspections of foreign facilities still suffer from many restrictions. DiLoreto does believe, however, that the situation is improving in many countries, as indicated by the recent agreement in China.

	There is also the issue of the dramatic increase in warning letters issued to foreign manufacturers that has occurred along with the rise in foreign inspections. DiLoreto expects these problems to be resolved once these manufacturers have been educated about GMP requirements and become familiar with the expectations of FDA. “It is not surprising that issues are being found at facilities that are being inspected for the first time. These facilities will implement the required improvements, and the number of citations will decline as more effective quality programs are put in place,” he observes.

	It is also important to remember, according to DiLoreto, that many of the FDA inspectors now on the job are still quite new. “It takes at least two years for an FDA inspector to be fully trained, because it take time for him/her to gain the practical experience needed for the job,” he says. “A large percentage of current FDA inspectors don ‘t have that two years of experience yet, and while new inspectors are on the learning curve, issues can arise,” DiLoreto continues. These difficulties, however, should also be resolved in the next few years, he notes.

, “Drug Safety: FDA Faces Challenges Overseeing the Foreign Drug Manufacturing Supply Chain,” Sept. 14, 2011 (Washington, DC).
	2. FDA, 

2015 Annual Report on Inspections of Establishments in FY 2014

, January 2015 (Rockville, MD).
	3. Department of Health and Human Services, 

Fiscal Year 2015 Food and Drug Administration Justification of Estimates for Appropriations Committees

, February 2014 (Washington, DC).
	4. Department of Health and Human Services, 

Fiscal Year 2016 Food and Drug Administration Justification of Estimates for Appropriations Committees

, Jan. 30, 2015 (Washington, DC).
	5. M. Mansour et al., “United States: FDA And China Agree To Collaborate On Inspections,” 


	When referring to this article, please cite as C. Challener, “FDA Steps Up Foreign Inspections,” 

FDA steps up inspections of foreign API manufacturers, thanks to new legislation and changes in policy.

Better Control of the API Supply Chain?

An integrated pilot plant tests heteronucleation and continuous crystallization.

Considering Continuous Crystallization

	For many reasons-from ease of administration to dosing accuracy to manufacturing efficiency-pharmaceutical manufacturers prefer to formulate their APIs as solid dosage drugs, and particularly tablets. There is significant room, however, for improvement of tableting processes.


	Lubricants (commonly magnesium stearate) affect the tableting process and the finished tablet. They not only reduce the compression force during tableting, but also prevent product buildup on tablet press tools and give the tablet a smooth surface. Too much lubricant can, however, reduce the hardness of the tablet to an undesired level, according to Sharon Nowak, business development manager with Coperion K-Tron Food & Pharmaceutical Industries. Traditionally, lubricants have been mixed with the solids used to form tablets, but this approach often leads to non-uniform distribution of the lubricant. To compensate, excess lubricant is used, which can negatively affect tablet properties.
	
	Recently, equipment has been developed that allows for spraying of the lubricant onto the tablet press tooling, allowing for significant reduction in the quantity of lubricant required. Original systems sprayed powdered lubricants on to the tablet press tooling to prevent sticking of the powder to the tool and die of the tablet press, according to Nowak. Importantly, these applications were done primarily volumetrically, with no measurement of the actual weight of the lubricant delivered. Magnesium stearate does not flow well, which can cause high variations in the feed rate with volumetric feeders because of inconsistent filling of the twin screws. As a result, there has been an increased demand for automated tablet press lubrication systems with highly accurate gravimetric feed designs, according to Nowak.

	“High accuracy twin-screw gravimetric feeders quantitatively deliver a specific amount of lubricant to the tablet. They also allow accurate determination of the amount of lubricant delivered to each tablet, even though the quantity of lubricant that ends up in the tablet granulation formulation is significantly decreased,” she observes. As a result, not only are the material handling properties of the granulation process improved, the overall dissolution rates of tablets can be increased. The lower quantities of lubricants required for tableting have also led to a need for lower and lower feed rate deliveries, according to Nowak. “For this reason, automated lubricant feeding systems today require highly accurate, specialized low-rate feeding,” she says.

	Coperion K-Tron’s solution uses patented load cell technology that continuously measures the weight of the lubricant and maintains a constant mass flow (weight per unit of time) by adjusting the speed of the twin-screw feeder. As a result, according to Nowak, the unit can be validated for a steady and uniform feed of lubricant to the tablet press. In addition, because the lubricant is delivered to the tools in a fraction of a second, the short-term accuracy is high. “With a nearly constant feed rate, it is possible to achieve uniform coating of the tablet tools and eliminate sticking problems, all with reduced stearate consumption and lower overall operating costs,” Nowak states.
	
	

Multi-tipped tooling and advanced coatings


	The key drivers in tablet manufacturing are the need to increase yield and capacity while reducing manufacturing costs and minimizing the space used and the time spent setting up each press, and increasing productivity has always been a challenge in modern tablet production, according to Steve Deakin, owner director of I Holland. That is why he believes the widespread use of multi-tipped tooling and the continued development of punch-and-die treatments and coatings have been great advances in the pharmaceutical industry.
	
	“Our ongoing development of multi-tip tooling is specifically driven by the desire to assist our customers in increasing productivity and capacity,” he says. Multi-tip punches allow the number of tablets per turret rotation to be multiplied by the number of tips on the punch. They also require less floor space, because more tablets can be produced with fewer tablet presses, leading to a reduction in overall plant running costs. “The development of a technology like multi-tip tooling is beneficial to many end users,” says Deakin.

	With respect to treatment and coating technologies, I Holland categorizes them based on their function: improving wear resistance, improving corrosion resistance, and improving anti-stick properties. “Treatments and coatings with these properties can help preserve the life of our punches and increase productivity for our customers,” Deakin comments. “The overall result is reduced press downtime and increased productivity, which is what every company wants,” he adds.


	Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology. Read the complete article by Cynthia Challener, with additional discussion of continuous manufacturing, systems integration, and modeling, in the 

Learn More from Sharon Nowak and Others at Interphex

 will host solid dosage manufacturing experts on the Innovation Stage. Come hear Sharon Nowak, Business Development Manager, Coperion K-Tron Food & Pharmaceutical Industries, speak about 

Optimization of Feeding and Conveying Technologies for Difficult Flowing Pharmaceutical Powders; 

Martin Hack, vice-president and general manager, L.B. Bohle, speak about 

Fluid Bed Technologies for Improved Processing; 

and Fred Murray, president, Korsch America, speak about 

Innovations for tablet tooling and presses improve quality and productivity.

Specialized Equipment Improves Tableting

New legislation and changes in policy at FDA are leading to better control of the API supply chain.